Process for preparing indoline-2-carboxylic acids via alpha-hydroxy-2-nitrobenzenepropanoic acid

ABSTRACT

Disclosed herein is a process for obtaining indoline-2-carboxylic acid (or derivatives thereof) comprising the following steps: (a) reducing α-oxo-2-nitrobenzenepropanoic acid to α-hydroxy-2-nitrobenzenepropanoic acid, (b) replacing the hydroxyl group of the latter with a chlorine atom utilizing a selected Vilsmeier chlorinating reagent at temperatures of at least 20° C., (c) reducing the nitro group of the resulting α-chloro-2-nitrobenzenepropanoic acid to obtain α-chloro-2-aminobenzenepropanoic acid, and (d) cyclizing the latter in aqueous base to form the desired indoline-2-carboxylic acid. Alternately, steps (c) and (d) may be combined in a one pot step by using, for example, a Raney nickel-hydrazine reducing medium.

This is a continuation of application Ser. No. 565,083 filed Dec. 23,1983, now abandoned.

This invention describes a process for making indoline-2-carboxylicacids of the formula ##STR1## wherein X is hydrogen, chlorine, bromine,C₁₋₄ alkyl or C₁₋₄ alkoxy.

The overall process is shown in the following diagram: ##STR2## Steps B,D and E in this process are also novel and patent protection is soughtfor them as well as for the overall process. In addition, theintermediate 2-amino-α-chlorobenzenepropanoic acids (V) are novel andpatent protection is likewise sought for these compounds.

BACKGROUND OF THE INVENTION

Indoline-2-carboxylic acids have heretofore been prepared by firstforming the corresponding indole-2-carboxylic acid and then reducing the2,3-double bond. The chief drawback in such preparations has been thelack of a satisfactory process for reducing the 2,3-double bond.

One of the methods of obtaining the indole-2-carboxylic acid to bereduced has been via the Reissert synthesis wherein o-nitrophenylpyruvicacid (II above where X is hydrogen) is reductively cyclized directly tothe indoline-2-carboxylic acid using zinc and acetic acid or ferroussulfate and ammonium hydroxide. See Weissberger, ed., The Chemistry ofHeterocyclic Compounds, Vol. 25, part 1, pp. 396-399 (WileyInterscience, New York, 1972).

Three methods are reported for reducing indole-2-carboxylic acid toindoline-2-carboxylic acid. Hudson and Robertson, Australian Journal ofChemistry, 20, 1935-41 (1967), first converted the acid to the amide andreduced the 2,3-double bond of the amide using phosphoniumiodide/hydriodic acid. They then converted the resultingindoline-2-carboxamide to the desired indoline-2-carboxylic acid byhydrolysis. Y. Omote et al., Nippon Kagaku Zasshi, 87, 760 (1966), alsoreported an indirect reduction. [See Stanton et al., Journal ofMedicinal Chemistry, 26, 1267-77 at 1268 (1983)]. In this method theindole-2-carboxylic acid was first converted to the N-acetyl derivativewhich was reduced by hydrogenation at atmospheric pressure in thepresence of platinum oxide. The resulting N-acetyl-indoline-2-carboxylicacid was then hydrolized to remove the acetyl group. Corey et al.,Journal of the American Chemical Society, 92, 2476-2488, at 2480 (1970),directly reduced indole-2-carboxylic acid ethyl ester using excess dryhydrogen chloride gas and tin and absolute ethanol in a sealed bomb.

Applicants' new process for producing indoline-2-carboxylic acids avoidsthese indirect and inefficient reductions by cyclization of their newintermediate α-chloro-2-aminobenzenepropanoic acids V to yield thedesired indoline-2-carboxylic acids directly.

The indoline-2-carboxylic acids of Formula I are useful as startingmaterials for the preparation ofN-(3-mercapto-2-alkyl-1-oxopropyl)-indoline-2-carboxylic acids andN-(2-substituted-1-oxoalkyl)-indoline-2-carboxylic acids thereof whichhave antihypertensive and angiotensin converting enzyme (ACE) inhibitoryproperties. These antihypertensive agents and ACE inhibitors aredisclosed, respectively, in U.S. Pat. No. 4,303,583, issued on Dec. 1,1981, to D. H. Kim and R. J. McCaully and in U.S. Pat. No. 4,350,633,issued on Sept. 21, 1982, also to D. H. Kim and R. J. McCaully.

DETAILED DESCRIPTION OF THE INVENTION

In step A of Applications' process, commercially availableα-oxo-2-nitrobenzenepropanoic acid [i.e. o-nitrophenylpyruvic acid] (II)is selectively reduced to give α-hydroxy-2-nitrobenzenepropanoic acid(III). Good yields are obtained in this selective reduction using sodiumborohydride as the reducing agent in a hydroxylic solvent, such asethanol or water.

In step B, the resulting α-hydroxy-2-nitrobenzenepropanoic acid (III) isreacted with a Vilsmeier chlorinating reagent in order to form anα-chloro-2-nitrobenzenepropanoic acid (IV) by replacement of thehydroxyl group with a chlorine atom. The Vilsmeier chlorinating reagentis formed from the combination of a chlorinating agent and an amide ofthe formula R₂ CONR₁ R₁, where R₁ and R₂ are preferably a methyl orethyl group. A suitable chlorinating agent may be selected from thionylchloride, oxalyl chloride, phosphorus oxychloride, phosphoruspentachloride, and sulfuryl chloride, with thionyl chloride beingespecially preferred. A suitable amide may be selected fromN,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, orN,N-diethylacetamide, with N,N-dimethylformamide (DMF) being especiallypreferred. The Vilsmeier reagent may be formed separately and then addedto the α-hydroxy-2-nitrobenzenepropanoic acid substrate, or theVilsmeier reagent may be formed in situ, usually by combining thesubstrate and the amide first and then adding the chlorinating agent.

In order to ensure chlorination at both the hydroxy and acyl sites ofthe substrate, thereby avoiding intermolecular condensation, the amideportion of the Vilsmeier reagent is preferably present in 2-6 moles permole of substrate. Good yields are obtained with 2-3 moles of amide permole of substrate. For the same reason, the chlorinating agent should bepresent in at least 2 moles per mole of substrate. Preferably thechlorinating agent is present in excess of 4 moles per mole of substrateand may be present in up to 34 moles per mole of substrate. Such largeexcesses are used particularly when no inert solvent is used for thereaction.

Accordingly, the reaction of step B can be run without a solvent or withan inert organic solvent such as dichloromethane, dichloroethane,chloroform, methylene chloride or ethylene chloride. Dichloromethane isthe preferred solvent. Additionally, temperatures above 20° C. arenecessary when reaction B is in progress. Preferably, the reactiontemperature is at least 25° C. and may vary up to about 50° C. dependingupon the particular Vilsmeier reagent and solvent used. A preferedtemperature range is 25°-35° C., and, at such temperatures, a reactiontime of 12-24 hours is preferred. Conveniently, an overnight reaction ofabout 18 hours at room temperatures of 25° C. is used.

The product IV, in which X is H [l it., S. Malinowski, Roczniki Chemii,26, 85 (1952)] was initially isolated by preparative HPLC as the freeacid. Later it was more conveniently isolated directly from the crudereaction mixture as the 2,6-dimethylpiperidine salt.

The nitro group of this α-chloro-2-nitrobenzenepropanoic acid IV may bereduced by various reducing agents. Conveniently, it was reduced withhydrogen over palladium on carbon in methanol at ambient temperature andpressure to give α-chloro-2-aminobenzene-propanoic acid (V).

The α-chloro-2-nitrobenzenepropanoic acid (V) or its amine salt is nextreduced in a basic medium to afford either the intermediateα-chloro-2-aminobenzenepropanoic acid (V) or the desiredindoline-2-carboxylic acid (I). The reduction may be done catalyticallyin the presence of standard hydrogenation catalysts such as palladium oncarbon in a hydrogen atmosphere, in which case the intermediate (V) isobtained. Alternatively, the reduction can be carried out with reducingagents that are compatible with a basic reaction medium, such as Raneynickel-hydrazine, in which case the desired indoline-2-carboxylic acid(1a) is obtained directly. In this case, reactions (steps) C and D arecombined in that they take place consecutively in the same reactionvessel. The work up steps of separating and isolating theα-chloro-2-aminobenzenepropanoic acid V are therefor avoided.

In those instances in which the intermediate (V) is generated andisolation is preferred, it is most convenient to isolate the compound asa salt formed with an alicyclic or cyclic amine. 2,6-Dimethylpiperidineis the preferred amine. Conversion of (V) to the indoline-2-carboxylicacid (I) is achieved by contacting a dispersion of (V) in a hydroxylicsolvent with an alkaline metal hydroxide. Isolation of the productfollows standard procedures.

X, as defined herein, may also include fluorine and "halogen" refers tofluorine, chlorine and bromine.

The following examples further illustrate the means and best mode forcarrying out the above-described invention

EXAMPLE 1 α-Hydroxy-2-Nitrobenzenepropanoic Acid

A. To a magnetically stirred solution of α-oxo-2-nitrobenzenepropanoicacid (40.00 g) in absolute ethanol (500 ml) cooled in ice water wasadded sodium borohydride (20.0 g) in portions at such a rate as tomaintain the temperature between 25 and 30°. The temperature of thesolution was maintained between 25°-30° for a further 4 hours after theaddition. The solution was evaporated to near dryness, and the residuewas dissolved in water. The solution was acidified with concentratedhydrochloric acid and extracted four times with ethyl acetate. Theorganic extract was washed twice with water and dried over magnesiumsulfate. Evaporation gave a syrup which was crystallized (seeding) fromdichloromethane-cyclohexane; yield 28.26 g (70%), m.p. 87°-90°.Recrystallization with decolorization from water gave 20.31 g. (50%) ofthe titled compound; m.p. 104°-105°; MH⁺ 212 (CI mode), λ_(max) ^(KBr)1715 (COOH), 3445 (OH) cm⁻¹ ; pmr (CDCl₃, DMSO-d.sub. 6) δ3.04-3.72 (8lines, AB part of an ABX system, --CH₂ --), 4.34-4.54 (q centered at4.45, width 12 Hz, symmetrically spaced, X part of ABX system,--CH(OH)), 7.28-7.68 (m, 3 aromatic protons and exchangeable OH),7.80-8.00 ("d" centered at 7.95, "J" 8 Hz, 1 aromatic proton).

Analysis for: C₉ H₉ NO₅, Calculated: C, 51.19; H, 4.30; H, 6.63, Found:C, 51.53; H, 4.39; N, 6.28.

B. Alternatively, the preceding compound was prepared as follows:

To a magnetically stirred suspension of α-oxo-2-nitrobenzenepropanoicacid (5.00 g) in water (75 ml) containing 1 drop of decyl alcohol wasadded sodium borohydride (2.50 g) in portions to maintain a temperaturebetween 45° and 50°. The resulting solution was then left at roomtemperature for 21/2 hours. The solution was acidified with concentratedhydrochloric acid and seeded. Stirring and cooling gave crude product;yield 5.01 g, m.p. 84°-90°. Recrystallization from water gave titledproduct; yield 2.63 g (52%), m.p. 95°-98° with spectral data as above.

Analysis for: C₉ H₉ NO₅, Calculated: C, 51.19; H, 4.30; H, 6.63, Found:C, 50.77; H, 4.24; N, 6.28.

EXAMPLE 2 α-Chloro-2-Nitrobenzenepropanoic Acid

To a magnetically stirred solution of α-hydroxy-2-nitrobenzenepropanoicacid (1.00 g, 4.74 mmol) in N,N-dimethylformamide (2 ml, 25.85 mmol)cooled in ice was added thionyl chloride (12 ml, 164.5 mmol) slowlydropwise. The cooling bath was removed and the solution was left at roomtemperature (20° C.) overnight. The solution was evaporated to a solid.Ice and dichloromethane were added and the mixture was stirredmagnetically for one hour, during which time it warmed to roomtemperature. The layers were separated and the organic phase was washedsix times with water. The dried (MgSO₄) solution was evaporated to asyrup which was subjected to an oil pump vacuum; yield 1.09 gExamination of the syrup on the μ-Bondapak C¹⁸ chromatographic column(Waters Associates) using a solvent system containing 90% of 0.1Nammonium acetate, pH 4.0 buffer and 10% acetonitrile revealed threecomponents. The major component, which was present to the extent of 74%of the mixture, was separated on a Waters Associates Prep. 500 unitusing a C¹⁸ cartridge and the solvent system mentioned above.Appropriate fractions were evaporated to a syrup below room temperature.The syrup was mixed with dilute hydrochloric acid and chloroform. Theorganic phase was washed twice with saturated brine and dried (MgSO₄).The solution was evaporated to a syrup which crystallized spontaneously(0.48 g, 44%). Crystallization from chloroform-cyclohexane gave 0.33 g(31%) of the titled product; m.p. 108°-109°; MH⁺ 230 (1 Cl, CI mode);λ_(max) ^(KBr) 1707, 1725 (COOH), pmr (CDCl₃) δ3.22-3.96 (8 lines, ABpart of an ABX system, --CH₂ --), 4.60-4.88 (q centered at 4.76, width14 Hz, "J" 6 Hz, X part of ABX system, >CH), 7.32-8.16 (m, aromatic).

Analysis for: C₉ H₈ NClO₄, Calculated: C, 47.08; H, 3.51; Cl, 15.44; N,6.10, Found: C, 47.14; H, 3.62; Cl, 15.20; N, 6.23.

S. Malinowski [Rocziniki Chemii 26, 85 (1952)] reported m.p. 109°-110°for the acid. It was found that the acid formed a crystalline2,6-dimethylpiperidine salt, m.p. 139°-141° (from ether), which wasutilized to isolate the titled acid as described below in Example 3.

EXAMPLE 3 α-Chloro-2-Nitrobenzenepropanoic Acid, 2,6-DimethylpiperidineSalt

To magnetically stirred N,N-dimethylformamide (6 ml, 77.6 mmol) cooledin ice was added thionyl chloride (36 ml, 493.5 mmol) slowly dropwise togenerate the Vilsmeier reagent. To the cold reagent was addedportionwise α-hydroxy-2-nitrobenzenepropanoic acid (3.00 g, 14.2 mmol).The solution was left at ice bath temperature for half an hour and thenleft at room temperature (about 20° C.) for 40 hours. The solution wasevaporated and the resulting solid was dissolved in dichloromethane. Thesolution was added cautiously to stirred ice and the mixture was stirredfor one hour, during which time it warmed to room temperature. Theorganic layer was washed with water (x 3), dried over magnesium sulfateand evaporated to a syrup which was subject to an oil pump vacuum; yield3.78 g. The syrup was dissolved in ether (50 ml) and2,6-dimethylpiperidine was added to neutrality (pH paper). Seeding withthe titled salt (prepared above from pureα-chloro-2-nitrobenzenepropanoic acid) and scratching followed bymagnetic stirring gave 2.58 g (53%) of crude titled product, m.p.134°-137°. The product was dissolved in methanol and the solution wasdecolorized. Evaporation gave a syrup which was crystallized by warmingin ether, followed by refrigeration; yield 2.20 g; m.p. 139°-140°, MH⁺230 (1 Cl, C.I. mode); λ_(max) ^(KBr) 1590, 1520 cm⁻¹ ; pmr (DMSO-d₆)δ1.17 (d, J_(Me),H 6Hz, Me), 1.24-1.84 (m, --CH₂ CH₂ CH₂ --), 2.76-3.16(bm, CH--NH--CH), 3.12-3.70 (8 lines AB part of an ABX system, --CH₂--CHCl), 4.16-4.36 (q centered at 4.27, width 14 Hz, "J" 6 Hz, X part ofan ABX system, --CHCl--), 7.38-7.76 (m, aromatic) 7.80-7.98 ("d"centered at 7.91; "J" 8 Hz, 1 aromatic proton).

Analysis for: C₉ H₈ ClNO₄ .C₇ H₁₅ N, Calculated: C, 56.06; H, 6.76; Cl,10.34; N, 8.17, Found: C, 56.09; H, 6.75; Cl, 9.95; N, 7.81.

EXAMPLE 4 α-Chloro-2-aminobenzenepropanoic Acid, 2,6-dimethylpiperidineSalt

α-Chloro-2-nitrobenzenepropanoic acid, 2,6-dimethylpiperidine salt (1.37g) was hydrogenated in methanol (100 ml) over 5% palladium on carbon(0.16 g) at ambient temperature and pressure. After the theoreticaluptake of hydrogen had been achieved the reaction was stopped and thecatalyst removed by filtration through analytical filter aid. Thesolution was evaporated below room temperature to a syrup which wascoevaporated with cyclohexane. The resulting syrup was seeded andstirred magnetically in ether. The resulting crystalline product wascollected and washed with ether; yield 1.09 g (87%); mp 120°-122°; MH⁺--H₂ O, 182 (1 Cl, CI mode ); λ_(max) ^(KBr) 3240, 3343, 3404 (NH),1627, 1579 cm⁻¹ ; pmr (DMSO-d₆) δ1.18 (d, J_(Me),H 6Hz, Me), 1.26-1.84(m, --CH₂ CH₂ CH₂ --), 2.66-3.36 (8 lines, AB part of an ABX system,--CH₂ --CHCl), 2.78-3.14 (bm overlapping ABX pattern, CH--NH--CH),4.12-4.30 (t centered at 4.21, width 14 Hz, "J" 7 Hz, X part of ABXsystem, >CHCl), 7.38-7.70 (m, 2 aromatic protons), 7.78-8.08 (m, 2aromatic protons). Analysis for: C₉ H₁₀ ClNO₂.C₇ H₁₅ N, Calculated: C,61.43; H, 8.05; Cl, 11.33; N, 8.95, Found: C, 61.36; H, 7.82; Cl, 11.43;N, 9.20.

EXAMPLE 5 2,3-Dihydro-1H-indole-2-carboxylic Acid

To 1 ml N sodium hydroxide and water (3 ml) under nitrogen at roomtemperature was added α-chloro-2-aminobenzenepropanoic acid,2,6-dimethylpiperidine salt (0.6257 g). After 15 minutes a further 1 mlof N sodium hydroxide was added and the solution was kept under nitrogenat room temperature overnight. The solution was filtered and evaporatedto slightly smaller volume. The solution was stirred magnetically, andthe pH of the solution was adjusted to a value of 3 by the dropwiseaddition of dilute hydrochloric acid. The product crystallized readily.After refrigeration the product was collected and washed twice withsmall volumes of ice cold water. The product was dried at roomtemperature in a vacuum over phosphorus pentoxide to give hydratedtitled compound; yield 0.233 g (71%); mp 154°-156°; MH⁺ 164 (CI mode);λ_(max) ^(KBr) 1615, 1580 cm⁻¹ ; pmr (DMSO-d₆); δ3.90-4.46 (7 lines, ABpart of an ABX system, --CH₂ --), 4.16-4.38 (q centered at 4.27, width16 Hz, "J" 6 Hz, X part of ABX system, >CHCO₂ H), 4.00-6.40 (bs NH₂ ⁺),6.44-6.68 (m, 2 aromatic protons) 6.80-7.10 (m, 2 aromatic protons).

Analysis for: C₉ H₉ NO₂. 0.1H₂ O, Calculated: C, 65.52; H, 5.62; N,8.49, Found: C, 65.42; H, 5.80; N, 8.30.

The spectral data of the compound were identical with those of materialprepared by previous methods.

EXAMPLE 6 α-Chloro-2-nitrobenzenepropanoic acid, 1-dimethylethyl ester

To magnetically stirred N,N-dimethylformamide (12 ml, 155.1 mmol) cooledin ice was added thionyl chloride (72 ml, 987.1 mmol) slowly dropwise togenerate the Vilsmeier reagent. To the cold reagent was addedportionwise α-hydroxy-2-nitrobenzenepropanoic acid (6.0 g, 28.4 mmol).The solution was left for half an hour at ice bath temperature and thenleft at room temperature overnight. Evaporation gave a solid which wassubjected to an oil pump vacuum. The residue was dissolved indichloromethane and added dropwise to t-butanol (150 ml) at ambienttemperature. The resulting solution, protected from moisture, was leftovernight at room temperature. The solution was evaporated to an oilwhich was subjected to an oil pump vacuum. The resulting oil wasdissolved in chloroform and applied to a column (50×3.8 cm) of silicagel (J. T. Baker) prepacked in chloroform. Elution was with chloroformand the fractionation was monitored by tlc on silica gel GF (Analtech)with chloroform as developer. Evaporation of appropriate fractions gavea major component (4.61 g of yellow oil) slightly contaminated with aslower component. The oil was dissolved in chloroform and applied to asecond column (52×3.2 cm) of silica gel prepacked in chloroform. Elutionwith chloroform gave fractions containing the major component freed fromits contaminant. Evaporation to smaller volume followed bydecolorization and solvent removal gave titled compound as a yellow oil;yield 3.17 g (39 %); MH⁺ 286 (1Cl, CI mode); λ_(max) ^(KBr) 1730 cm⁻¹(ester); pmr (CDCl₃) δ1.45 (s, t-Bu), 3.28-3.82 (8 lines, AB part of anABX system, --CH₂ --CHCl--), 4.42-4.68 (q centered at 4.57, width 14 Hz,X part of ABX system, "J" 6 Hz, >CH(Cl)-), 7.38-7.70 (m, 3 aromaticprotons), 7.98-8.12 (m, 1 aromatic proton).

Analysis for: C₁₃ H₁₆ ClNO₄, Calculated: C, 54.65; H, 5.64; Cl, 12.41;N, 4.90, Found: C, 53.89; H, 5.53; Cl, 12.28; N, 4.86.

Crystalline α-chloro-2-nitrobenzenepropanoic acid, 1-dimethylethyl ester

Chromatographically purified, syrupy, α-chloro-2-nitrobenzenepropanoicacid, 1-dimethylethyl ester, protected from light, crystallized on longstanding at room temperature. Trituration with heptane gave crystallinematerial, mp 53°-55° C. Recrystallization of 2.21 g of this materialfrom heptane gave 1.92 g of product, mp 54°-56° C. Spectral data were asrecorded previously.

Analysis for: C₁₃ H₁₆ ClNO₄, Calculated: C, 54.65; H, 5.64; Cl, 12.41;N, 4.90, Found: C, 54.75; H, 5.60; Cl, 12.28; N, 5.09.

EXAMPLE 7 α-Chloro-2-Nitrobenzenepropanoic Acid, 2,6-DimethylpiperidineSalt

To N,N-dimethylformamide (12 ml, 155.1 mmol) cooled in ice was addedthionyl chloride (72 ml, 987.1 mmol) slowly dropwise.α-Hydroxy-2-nitrobenzenepropanoic acid (6.00 g, 28.4 mmol) was added tothe cold solution and the resulting yellow solution was kept at ice bathtemperature for half an hour and then left at room temperature (25° ormore) overnight. The solution was evaporated to a syrup which wasdissolved in dichloromethane. The solution was added cautiously tostirred ice. The mixture was stirred for 1 hour during which time themixture was allowed to warm to room temperature. The organic extract waswashed (x4) with water, dried over magnesium sulfate and evaporated to asyrup which was subjected to an oil pump vacuum; yield=8.71 g. To thesyrup dissolved in ether (40 ml) was added 2,6-dimethylpiperidine untilthe solution was neutral (pH paper). Seeding and stirring gave 8.00 g oftitled product (82%); mp=139°-140°, MH⁺ 230 (1 Cl, C.I. mode); λ_(max)^(KBr) 1590, 1520 cm⁻¹ ; pmr (DMSO-d₆) δ1.17 (d, J_(Me),H 6Hz,Me)1.24-1.84 (m, --CH₂ CH₂ CH₂ --), 2.76-3.16 (bm, CH--NH--CH) 3.12-3.70 (8lines, AB part of an ABX system --CH₂ CHCl), 4.16-4.36 (q centered at4.27, width 14 Hz, "J" 6 Hz, X part of an ABX system --CHCl--),7.38-7.76 (m, aromatic) 7.80-7.98 ("D" centered at 7.91, "J" 8 Hz, 1aromatic proton).

Analysis for: C₉ H₈ ClNO₄.C₇ H₁₅ N, Calculated: C, 56.06; H, 6.76; N,8.17; Cl, 10.34, Found: C, 56.16; H, 6.65; N, 8.11; Cl, 9.95.

EXAMPLE 8 α-Chloro-2-nitrobenzenepropanoic acid 2,6-dimethylpiperidinesalt

To magnetically stirred N,N-dimethylformamide (2 ml, 25.8 mmol) cooledin ice was added slowly dropwise thionyl chloride (3 ml, 41.1 mmol), andthe resulting cold Vilsmeier reagent was diluted with dichloromethane(10 ml). α-Hydroxy-2-nitrobenzenepropanoic acid (2.00 g, 9.47 mmol),followed by an additional 2 ml of dichloromethane was added. Themixture, protected from moisture, was stirred at room temperature (25°C.) overnight. The resulting solution was evaporated to a syrup. Thesyrup was dissolved in dichloromethane and the solution was added tostirred ice. The mixture was stirred for 1 hour during which time itwarmed to room temperature. The dichloromethane solution was separatedand washed (X4) with water and dried (MgSO₄). Evaporation gave a syrupwhich was subjected to an oil pump vacuum for half an hour. The syrupwas dissolved in ether and 2,6-dimethylpiperidine was added toapproximate neutrality (pH 9 with pH paper). The crude titled product[2.36 g (81%), mp 138-140° C.]crystallized readily. Recrystallization(methanol-ether) with decolorization (Nuchar C-190N) gave pure product,mp 141°-143° C.

Analysis for: C₉ H₈ ClNO₄ C₇ H₁₅ N, Calculated: C, 56.06; H, 6.76; Cl,10.34; N, 8.17, Found: C, 55.90; H, 6.72; Cl, 10.32; N, 8.28.

EXAMPLE 9 2,3-Dihydro-1H-indole-2-carboxylic acid fromα-chloro-2-nitrobenzenepropanoic acid 2,6-dimethylpiperidine salt usingaqueous hydrazine in the presence of sponge nickel

To a magnetically stirred suspension of α-chloro-2-nitrobenzenepropanoic2,6-dimethylpiperidine salt (1.714 g, 5.0 mmol) and Raney nickel (0.25g, Davison No. 28) in water (7 ml) under an atmosphere of nitrogen wasadded dropwise hydrazine hydrate (1.5 ml, 55.2 mmol) over the course of1 hour. The temperature of the reaction was allowed to rise to between30 and 35° C. during this period. (Waterbath cooling was used whennecessary). The starting material gradually dissolved during thisperiod. Stirring was continued for a further 2.5 hours. The mixture wasfiltered throuhg Celite and the purple filtrate was cooled in ice,magnetically stirred, and acidified to pH 2 (pH paper) with concentratedhydrochloric acid. A layer of ether was added to dissolve the initiallyprecipitated impurities. The titled product then crystallized readily.Collection on a filter, followed by consecutive washings with ether, twosmall aliquots of ice-cold water and ether gave 0.32 g (39%) of thetitle product, mp 147°-149° C.

Analysis for: C₉ H₉ NO₂ 0.2H₂ O, Calculated: C, 64.82; H, 5.68; N, 8.40,Found: C, 64.89; H, 5.47; N, 8.60. IR, ¹ H NMR and mass spectral datawere consistent for the above structure.

EXAMPLE 10 α-Chloro-2-nitrobenzenepropanoic Acid

To a magnetically stirred N,N-dimethylformamide (20 ml, 258.5 mmol)cooled in ice was added slowly dropwise thionyl chloride (30 ml, 411.2mmol). To the resulting cold Vilsmeier reagent was added dichloromethane(100 ml), α-hydroxy-2-nitrobenzenepropanoic acid (20.0 g, 94.7 mmol) anda further 50 mL of dichloromethane as a rinse. The mixture, protectedfrom extraneous moisture, was stirred at room temperature until solutionwas achieved and the solution was left at room temperature (25° C.)overnight. The solution was poured onto stirred ice and the mixturestirred for 1 hour during which time it warmed to room temperature. Thedichloromethane layer was separated, washed thrice with water, dried(MgSO₄) and evaporated to a syrup. The syrup was concentrated further at40° C. under oil pump vacuum to remove traces of N,N-dimethylformamide.The resulting syrup was stirred magnetically with water while cooling inice. The resulting solid was ground in a mortar and collected on afilter. The solid was then stirred magnetically with water, collected ona filter and washed with water. Drying under vacuum over phosphoruspentoxide at room temperature provided 19.60 g (90%) of titled product,mp 107°-109° C.

Analysis for: C₉ H₈ ClNO₄, Calculated: C, 47.08; H, 3.51; Cl, 15.44; N,6.10, Found: C, 47.29; H, 3.51; Cl, 15.06; N, 6.20.

Spectral data were as previously described.

EXAMPLE 11 Conversion of Crystalline α-Chloro-2-nitrobenzenepropanoicAcid into its 2,6-dimethylpiperidine salt

Crystalline α-chloro-2-nitrobenzenepropanoic acid (19.51 g) wasdissolved in ether (100-150 ml) and the solution filtered throughcelite. To the filtrate was added 2,6-dimethylpiperidine until pH 9 (pHpaper). Crude product [28.66 g, (98%), mp=138-140° C.] crystallizedreadily. Recrystallization with decolorization (Nuchar C-190N) frommethanol-ether gave pure product, mp=141°-143° C.

Analysis for: C₉ H₈ ClNO₄.C₇ H₁₅ N, Calculated: C, 56.06; H, 6.76; Cl,10.34; N, 8.17, Found: C, 56.29; H, 6.75; Cl, 10.29; N, 8.44.

What is claimed is:
 1. A process for producing an indoline-2-carboxylicacid of the formula: ##STR3## wherein X is hydrogen, chlorine, bromine,C₁₋₄ alkyl or C₁₋₄ alkoxy, which comprises,(a) reacting anα-hydroxy-2-nitrobenzenepropanoic acid of the formula: ##STR4## whereinX is as defined above, with a Vilsmeier chlorinating reagent in whichthe chlorinating agent thereof is selected from a group consisting ofthionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphoruspentachloride and sulfuryl chloride and the amide thereof is selectedfrom a group consisting of dimethylformamide, diethylformamide,dimethylacetamide and diethylacetamide, said reaction being run attemperatures of at least 20° C., in order to obtain anα-chloro-2-nitrobenzenepropanoic acid of the formula: ##STR5## (b)reducing the nitro group of said α-chloro-2-nitrobenzenepropanoic acid(IV) to an amino group; and (c) cyclizing the resultingα-chloro-2-aminobenzenepropanoic acid in aqueous base.
 2. A processaccording to claim 1 in which steps b and c are combined.
 3. A processaccording to claim 1 in which the chlorinating agent is thionylchloride.
 4. A process according to claim 1 in which the amide isN,N-dimethylformamide.
 5. A process according to claim 1 in which thetemperature in step a is at least 25° C.
 6. A process according to claim1 in which X is hydrogen.
 7. A process according to claim 1 in which theα-hydroxy-2-nitrobenzenepropanoic acid starting material (III) isobtained by selectively reducing a α-oxo-2-nitrobenzenepropanoic acid ofthe formula: ##STR6## wherein X is defined in claim 1, using sodiumborohydride as a reducing agent in a hydroxylic solvent.